title: Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8+ T cells combined with a DC vaccine.
abstract: The success of cancer immunotherapy is limited by potent endogenous immune-evasion mechanisms, which are at least in part mediated by transforming growth factor-β (TGF-β). The E3 ubiquitin ligase Cbl-b is a key regulator of T cell activation and is established to regulate TGF-β sensitivity. cblb-deficient animals reject tumors via CD8(+) T cells, which make Cbl-b an ideal target for improvement of adoptive T-cell transfer (ATC) therapy. In this study, we show that cblb-deficient CD8(+) T cells are hyper-responsive to T-cell receptor (TCR)/CD28-stimulation and are in part protected against the negative cues induced by TGF-β in vitro. Notably, adoptive transfer of polyclonal, non-TCR transgenic cblb-deficient CD8(+) T cells is not sufficient to reject B16-ova or EG7 tumors in vivo. Thus, cblb-deficient ATC requires proper in vivo re-activation by a dendritic cell (DC) vaccine. In strict contrast to ATC monotherapy, this approach delayed tumor outgrowth and significantly increased survival rates, which is paralleled by increased CD8(+) T-cells infiltration to the tumor site and enrichment of ova-specific and interferon-γ (IFN-γ)-secreting CD8(+) T cell in the draining lymph node (LN). Moreover, CD8(+) T cells from cblb-deficient mice vaccinated with the DC vaccine show increased cytolytic activity in vivo. In summary, our data using cblb-deficient polyclonal, non-TCR-transgenic adoptively transferred CD8(+) T cells into immuno-competent non-lymphodepleted recipients suggest that targeting Cbl-b might serve as a novel 'adjuvant approach', suitable to augment the effectiveness of established anti-cancer immunotherapies.
authors.affiliation: Tyrolean Cancer Research Institute, Innsbruck Medical University, Tyrol, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Lutz-Nicoladoni
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wallner
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pircher
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Wolf
authors.forename: Günther
authors.initials: G
authors.lastname: Gastl
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019496:Cancer Vaccines; C118387:Cblb protein, mouse; D016207:Cytokines; D016212:Transforming Growth Factor beta; D050721:Proto-Oncogene Proteins c-cbl